School of Biosciences, College of Biomedical and Life Sciences, Cardiff University, Cardiff CF10 3AX, UK.
Institute of Life Science, Swansea University Medical School, Swansea University, Swansea SA2 8PP, UK.
Biomolecules. 2022 Jul 26;12(8):1030. doi: 10.3390/biom12081030.
The ryanodine receptor (RyR2) has a critical role in controlling Ca release from the sarcoplasmic reticulum (SR) throughout the cardiac cycle. RyR2 protein has multiple functional domains with specific roles, and four of these RyR2 protomers are required to form the quaternary structure that comprises the functional channel. Numerous mutations in the gene encoding RyR2 protein have been identified and many are linked to a wide spectrum of arrhythmic heart disease. Gain of function mutations (GoF) result in a hyperactive channel that causes excessive spontaneous SR Ca release. This is the predominant cause of the inherited syndrome catecholaminergic polymorphic ventricular tachycardia (CPVT). Recently, rare hypoactive loss of function (LoF) mutations have been identified that produce atypical effects on cardiac Ca handling that has been termed calcium release deficiency syndrome (CRDS). Aberrant Ca release resulting from both GoF and LoF mutations can result in arrhythmias through the Na/Ca exchange mechanism. This mini-review discusses recent findings regarding the role of RyR2 domains and endogenous regulators that influence RyR2 gating normally and with GoF/LoF mutations. The arrhythmogenic consequences of GoF/LoF mutations will then be discussed at the macromolecular and cellular level.
兰尼碱受体（RyR2）在控制心肌细胞收缩周期内肌浆网（SR）钙离子释放中起着至关重要的作用。RyR2 蛋白具有多个具有特定功能的功能域，其中四个 RyR2 三聚体形成构成功能性通道的四级结构。已经发现编码 RyR2 蛋白的基因中有许多突变，其中许多与广泛的心律失常性心脏病有关。功能获得性突变（GoF）导致通道过度活跃，从而导致过度自发的 SR 钙离子释放。这是遗传性综合征儿茶酚胺多形性室性心动过速（CPVT）的主要原因。最近，已经发现了罕见的功能丧失性（LoF）突变，这些突变对心脏钙离子处理产生了非典型的影响，这种影响被称为钙释放缺陷综合征（CRDS）。由于 GoF 和 LoF 突变导致的异常钙离子释放，可通过钠/钙交换机制导致心律失常。本综述讨论了 RyR2 结构域和内源性调节剂的最新发现，这些调节剂通常会影响 RyR2 的门控，以及在 GoF/LoF 突变时的作用。然后将在大分子和细胞水平上讨论 GoF/LoF 突变的致心律失常后果。
